Dual Function of RGD-Modified VEGI-192 for Breast Cancer Treatment

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• 作者：Jueheng Wu ; Yi Jiang ; Wan Yang ; Zhenjian He ; Shiyu Meng ; Qianhui Zhang ; Min Lin ; Henan Zhang ; Weifeng Li ; Yaochao Yang ; Yiqun Jia ; Liang Qian ; Dihan Lu ; Wenjia Cai ; Guotian Luo ; Yesong Wang ; Xun Zhu ; Mengfeng Li
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：April 18, 2012
• 年：2012
• 卷：23
• 期：4
• 页码：796-804
• 全文大小：492K
• 年卷期：v.23,no.4(April 18, 2012)
• ISSN：1520-4812

文摘

Identification of endogenous angiogenesis inhibitors has led to development of an increasingly attractive strategy for cancer therapy and other angiogenesis-driven diseases. Vascular endothelial growth inhibitor (VEGI), a potent and relatively nontoxic endogenous angiogenesis inhibitor, has been intensively studied, and this work shed new light on developing promising anti-angiogenic strategies. It is well-documented that the RGD (Arg-Gly-Asp) motif exhibits high binding affinity to integrin 伪_v尾₃, which is abundantly expressed in cancer cells and specifically associated with angiogenesis on tumors. Here, we designed a fusion protein containing the special RGD-4C motif sequence and VEGI-192, aimed at offering more effective multiple targeting to tumor cells and tumor vasculature, and higher anti-angiogenic and antitumor efficacy. Functional tests demonstrated that the purified recombinant human RGD-VEGI-192 protein (rhRGD-VEGI-192) potently inhibited endothelial growth in vitro and suppressed neovascularization in chicken chorioallantoic membrane in vivo, to a higher degree as compared with rhVEGI-192 protein. More importantly, rhRGD-VEGI-192, but not rhVEGI-192 protein, could potentially target MDA-MB-435 breast tumor cells, significantly inhibiting growth of MDA-MB-435 cells in vitro, triggered apoptosis in MDA-MB-435 cells by activation of caspase-8 as well as caspase-3, which was mediated by activating the JNK signaling associated with upregulation of pro-apoptotic protein Puma, and consequently led to the observed significant antitumor effect in vivo against a human breast cancer xenograft. Our study indicated that the RGD-VEGI-192 fusion protein might represent a novel anti-angiogenic and antitumor strategy.